Project Summary ? Project 1 In this project we are studying how the communication between brain structures is changed in a mouse model of Parkinson's disease, compared to normal control mice. In particular, an important output pathway of the ba- sal ganglia is directed towards the motor cortex. This pathway passes through the ventral motor thalamus be- fore it reaches cortex. The main hypothesis of this research is that processing of basal ganglia signals in motor thalamus is altered in the parkinsonian state. We will address this hypothesis in three specific aims that exam- ine changes in the cellular and signal processing properties of neurons in the motor thalamus in the parkin- sonian condition, using the 6-hydroxydopamine lesion model of dopamine depletion in mice. In aim 1 we will analyze in a brain slice preparation which properties of thalamic neurons and synaptic inputs are changed in the parkinsonian condition using electrophysiological intracellular recordings. In aim 2 we will examine with electrophysiological recordings from neurons in the motor thalamus of awake behaving mice whether electrical activity patterns in parkinsonian mice differ from those in control animals during motor behavior. We will also use optogenetic stimulation techniques to trace specific signals along the basal ganglia-thalamocortical route. These stimulation techniques will also be studied with respect to their potential use as counteracting pathologi- cal patterns of activity seen in the parkinsonian animals. Finally, in aim 3, we will synthesize the results from aims 1 and aim 2 by building a detailed computer model of how neurons in the motor thalamus of parkinsonian mice process input from the basal ganglia and how this differs from the normal condition. We will test the validi- ty of this model with accompanying brain slice experiments, in which real neurons are subjected to the same synaptic input patterns that are used in the computer simulations. This allows for a direct comparison between spiking activity patterns generated by the computer model and those seen in recordings. This research will result in new insights concerning the mechanisms that lead to the expression of patho- logical neural activity patterns in the parkinsonian state. In particular little is known about the involvement of the motor thalamus in the pathophysiology of parkinsonism, and our results will make a substantial contribution to filling this knowledge gap. Further, our research results are expected to inform us about potential new tech- niques of optical deep brain stimulation with a positive effect on thalamic signal integration that could amelio- rate parkinsonian signs and symptoms. Our computer model will be made publicly available and will allow oth- er researchers to improve brain network models of how different pharmacological and deep brain stimulation interventions affect basal ganglia-thalamocortical circuitry and provide therapeutic function. This project is high- ly synergistic with project 2, which address parkinsonian pathology in the same circuit in a non-human primate system closer to the human disorder, while our rodent studies can provide more mechanistic detail. The ana- tomical studies in project 3 in turn will allow a close comparison of rodent and primate circuitry.